This is a competing renewal application for a Senior Scientist Award (K0-5) to continue research on the biological and behavioral aspects of substance abuse. The proposed research is based on several grant awards currently funded by NIDA, NIH. I am Principal Investigator on four awards: (1) a Program Project designed to evaluate new strategies for cocaine treatment medications in basic preclinical and clinical studies; (2) an R01 award for preclinical studies of the interactions between cocaine and opioid drugs with different receptor selectivities; (3) an R01 award to study the influence of gonadal steroid hormones on the reinforcing and discriminative stimulus effects of cocaine and (4) a contract concerned with the assessment of potential treatment medications in rhesus monkeys. In addition, I am co-investigator on an R01 award designed to evaluate the analgesic and abuse-related effects of delta opioids; an R01 award concerned with the synthesis and evaluation of mixed action kappa/mu opioids and a contract to assess potential cocaine treatment medications in rats. I am also co-investigator on a NIDA training grant and responsible for mentoring young scientists. Many of these multidisciplinary clinical and pre-clinical studies are concerned with the neurobiology of cocaine abuse from an endocrine perspective. The influence of gonadal steroid hormones on the reinforcing and discriminative stimulus effects of cocaine is being studied in non-human primates. The temporal pattern of cocaine's acute effects on anterior pituitary, gonadal and adrenal hormones is being examined in men and women, and in non-human primates. We hypothesize that the rapid co-modulatory interactions between cocaine and the hypothalamic-pituitary-gonadal and adrenal axes may contribute to cocaine's abuse-related effects and could suggest new approaches to treatment. The effects of mu, kappa and delta opioids on cocaine self-administration are being evaluated in preclinical behavioral pharmacology studies. In related studies, the effects of dopaminergic and opioid drug combinations on the abuse-related effects of cocaine and heroin "speedballs" are being evaluated. We hypothesize that medication combinations will be more effective in decreasing "speedball" abuse than single medications alone. Proposed plans for professional growth include continued study of endocrinology, brain imaging and computer science as well as study of two new directions in our research program that involve collaborative studies in medicinal chemistry and immunology.